Mitochondria are dynamic organelles, remodeling and exchanging contents during cyclic fusion and fission. Mitochondria fuse to transfer genetic information and promote mutual repair through content exchange. Mitochondrial outer membrane tethering and fusion is mediated by mitofusins (Mfn) 1 and 2 (Santel, 2006, Biochim Biophys Acta, 2006, 1763:490-499) is essential for embryonic development (Chen et al., 2003, J Cell Biol, 160:189-200; Kasahara et al., 2013, Science, 342:734-737) and tissue homeostasis (Chen et al., 2007, Cell, 130:548-562; Chen et al., 2010, Cell, 141:280-289; Song et al., 2015, Cell Metab, 21:273-285). In mammalian cells mitochondrial fission increases in response to injury and during programmed cells death. Mitochondrial fusion opposes fission and is essential for cell health (Chan, 2012, Annu Rev Genet, 46:265-287). Multiple mutations that provoke Mfn2 dysfunction can cause the untreatable neurodegenerative condition, Charcot Marie Tooth disease type 2A (CMT2A) (Bombelli et al., 2014, JAMA Neurol, 71:1036-1042). Absence of non-genetic means for regulating mitofusins has limited development of therapeutically effective approaches to treat or prevent CMT2A and other diseases causally linked to disturbances in mitochondrial fusion.
It has not been possible to directly modulate mitochondrial fusion, in part because the structural basis of mitofusin function is incompletely understood. Modeling, and rational design and data presented herein provide evidence that Mfns adopt either a fusion-constrained or a fusion-permissive molecular conformation directed by specific intramolecular binding interactions. Supportive studies demonstrate that Mfn1- and Mfn2-dependent mitochondrial fusion can be positively and negatively regulated by targeting these conformational transitions. Based on this model, a cell-permeant peptide was engineered that destabilizes the fusion-constrained Mfn state and promotes the fusion-permissive Mfn conformation. Application of this peptide construct to cultured cells harboring CMT2A gene defects reverses mitochondrial fragmentation and depolarization. The relationship between Mfn1 and Mfn2 conformational plasticity and mitochondrial dynamism uncovers a central molecular mechanism regulating mitochondrial fusion that can be manipulated to correct mitochondrial pathology in conditions such as CMT2A wherein defective mitochondrial dynamics is a contributory factor. Accordingly, the present disclosure provides compositions and methods for treating disorders related to defective mitochondrial fusion.